Disease-Modifying Treatments and Time to Loss of Ambulatory Function in Patients With Primary Progressive Multiple Sclerosis
Authors: Emilio Portaccio, Mattia Fonderico, Pietro Iaffaldano, Luisa Pastò, Lorenzo Razzolini, Angelo Bellinvia, Giovanna De Luca, Paolo Ragonese, Francesco Patti, Vincenzo Brescia Morra, Eleonora Cocco, Patrizia Sola, Matilde Inglese, Giacomo Lus, Carlo Pozzilli, Davide Maimone, Alessandra Lugaresi, Paola Gazzola, Giancarlo Comi, Ilaria Pesci, Daniele Spitaleri, Marta Rezzonico, Marika Vianello, Carlo Avolio, Francesco O. Logullo, Franco Granella, Marco Salvetti, Mauro Zaffaroni, Giuseppe Lucisano, Massimo Filippi, Maria Trojano, Maria Pia Amato, Vincenzo Di Lazzaro, Umberto Aguglia, Tiziana Tassinari, Simonetta Venturi, Simonetta Galgani, Simone Tonietti, Sergio Parodi, Salvatore Cottone, Rocco Totaro, Roberto Bergamaschi, Roberto Balgera, Renato Mantegazza, Raffaella Clerici, Patrizia Perrone, Paola Valentino, Paola Cavalla, Paola Banfi, Nicola Renato Pizio, Michela Bruzzone, Maurizio Leone, Maurizia Gatto, Mario Di Napoli, Mariarosa Rottoli, Maria Teresa Ferrò, Maria Luisa Piras, Maria Grazia Grasso, Marco Rovaris, Marco Ronzoni, Lorenzo Capone, Leonardo Sinisi, Guido Cavaletti, Giuseppe Santuccio, Giuseppe Salemi, Gioacchino Tedeschi, Giancarlo Di Battista, Franco Valzania, Francesco D'Andrea, Francesco Corea, Francesca De Robertis, Fabio Bandini, Enrico Millefiorini, Elio Scarpini, Dott Ssa Maria Merello, Dott Ssa Aurora Fuiani, Diego Centonze, Davide Nasuelli, Cristoforo Comi, Ciro Florio, Carlo Piantadosi, Bruno Passarella, Antonio Bertolotto, Alessandra Protti
Journal: JAMA Neurology (2022)

Except for ocrelizumab, treatment options in primary progressive multiple sclerosis (PPMS) are lacking.To investigate the effectiveness of DMTs on the risk of becoming wheelchair dependent in a real-world population of patients with PPMS.This was a multicenter, observational, retrospective, comparative effectiveness research study. Data were extracted on November 28, 2018, from the Italian multiple sclerosis register and analyzed from June to December 2021. Mean study follow-up was 11 years. Included in the study cohort were patients with a diagnosis of PPMS and at least 3 years of Expanded Disability Status Scale (EDSS) evaluations and 3 years of follow-up.The risk of reaching an EDSS score of 7.0 was assessed through multivariable Cox regression models.Patients who received DMT before the outcome were considered treated. DMT was assessed as a time-dependent variable and by class of DMT (moderately and highly effective).From a total of 3298 patients with PPMS, 2633 were excluded because they did not meet the entry criteria for the phase 3, multicenter, randomized, parallel-group, double-blind, placebo-controlled study to evaluate the efficacy and safety of ocrelizumab in adults with PPMS (ORATORIO) trial. Among the remaining 665 patients (mean [SD] age, 43.0 [10.7] years; 366 female patients [55.0%]), 409 were further selected for propensity score matching (288 treated and 121 untreated patients). In the matched cohort, during the study follow-up, 37% of patients (152 of 409) reached an EDSS score of 7.0 after a mean (SD) follow-up of 10.6 (5.6) years. A higher EDSS score at baseline (adjusted hazard ratio [aHR], 1.32; 95% CI, 1.13-1.55; P < .001), superimposed relapses (aHR, 2.37; 95% CI, 1.24-4.54; P = .009), and DMT exposure (aHR, 1.75; 95% CI, 1.04-2.94; P = .03) were associated with a higher risk of an EDSS score of 7.0, whereas the interaction term between DMT and superimposed relapses was associated with a reduced risk of EDSS score of 7.0 (aHR, 0.33; 95% CI, 0.16-0.71; P = .004). Similar findings were obtained when treatment according to DMT class was considered and when DMT was included as a time-dependent covariate. These results were confirmed in the subgroup of patients with available magnetic resonance imaging data.Results of this comparative effectiveness research study suggest that inflammation also occurs in patients with PPMS, may contribute to long-term disability, and may be associated with a reduced risk of becoming wheelchair dependent by current licensed DMTs.